This invention relates to novel pharmaceutical combinations comprising .alpha.-fluoromethylhistidine (FMH) and one or more non-steroidal anti-inflammatory/analgesic drugs (NSAID) particularly indomethacin, aspirin, diflunisal and naproxen. Unexpectedly, these novel combinations exhibit synergistic improvements over either of the separate component alone in the treatment of inflammation and pain. They are superior in terms of both more rapid onset of action and higher efficacy.
Non-narcotic analgesics, also known as non-steroidal anti-inflammatory drugs (NSAID), are widely administered orally in the treatment of mild to moderate pain. Within this class, the compounds vary widely in their chemical structure and in their biological profiles as analgesics, anti-inflammatory agents and antipyretic agents. Aspirin, acetaminophen and phenacetin have long been among the most commonly used members of this group; more recently, however, a large number of alternative non-narcotic agents offering a variety of advantages over the earlier drugs have been developed. Tolerance or addiction to these drugs is not generally a problem with their continuous use in the treatment of pain, acute or chronic inflammatory diseases, (notably, rheumatoid arthritis and osteoarthritis, dysmenorrhea); However, these new drugs generally have a higher potential for adverse side-effects. Furthermore, their effectiveness usually reaches a plateau at the upper limits of their effective dose ranges above which administration of additional drug does not increase the analgesic or anti-inflammatory effect. Among the newer compounds in the non-narcotic analgesic/non-steroidal anti-inflammatory group are compounds such as indomethacin (INDOCIN), diflunisal (DOLOBID), zomepirac sodium (ZOMAX), ibuprofen (MOTRIN), naproxen (NAPROSYN), fenoprofen (NALFON), piroxicam (FELDENE), flurbiprofen, mefenamic acid (PONSTEL) and sulindac (CLINORIL). See Physician's Desk Reference, 35th edition, 1981, and The Merck Index, 9th edition, Merck & Co., Rahway, N.J. (1976), for information on specific nonsteroidal anti-inflammatory agents.
.alpha.-Fluoromethylhistidine is a known compound being described in U.S. Pat. No. 4,325,961 issued to J. Kollonitsch et al. on Apr. 20, 1982. The compound inhibits mammalian histidine decarboxylase in vivo and thereby decreases considerably histamine levels in the body for a prolonged period.
Normally, in the classical carrageenan foot edema assay using the Sprague-Dawley male rat, (Winter et al, Proc. Soc. Exp. Biol., 111, 544 1962), .alpha.-fluoromethylhistidine is ineffective in blocking inflammation induced by carrageenan although pretreatment of the rats with .alpha.-fluoromethylhistidine one and a half days prior to carrageenan significantly inhibited the hindpaw edema. However, when .alpha.-fluoromethylhistidine is used in combination with a NSAID such as indomethacin, greater anti-inflammatory effect was achieved than either agent acting alone. Such an unexpected potentiating effect was observed even at lower dose levels of both components.
Accordingly, it is the object of the present invention to provide a synergistic combination of .alpha.-fluoromethylhistidine and one or more NSAIDs for use in eliciting anti-inflammatory responses more effectively and rapidly than any of the components alone.
Another object of the invention is to provide pharmaceutical compositions for the administration of these synergistic combinations.
Still a further object of this invention is to provide an improved method of treating pain and inflammatory conditions by administering a sufficient amount of the novel combinations in a mammalian species in need of such treatment.